Impact of Aging on CD4 Immunity to Viruses. In the elderly, influenza results in high morbidity and mortality. Current subunit vaccines are often ineffective in the aged population and they at best provide protection for only one year. Defining the nature of the defect in the response of the aged immune system and determining how the defect impact effective responses is extremely difficult in man because the population is genetically diverse, so large numbers of subjects are needed, and because manipulations designed to define mechanisms are not possible. In mi we can determine precisely whether individual subsets of cells are impaired, what mechanisms are compromised and how defects might be reversed. We have reported that CD4 T cell responses decline with aging, resulting in profoundly reduced primary effector generation, memory generation and antibody production. We have developed a T cell receptor transgenic model in which we can evaluate CD4 T cell defects precisely, by transferring young and aged naive CD4 T cells to young adoptive hosts, immunizing and following the response of the donor cells in situ. We propose to study the impact of aging on responses of CD4 to influenza viruses in this model. We will determine exactly how the response is compromised by aging and importantly whether adjuvants and vaccination protocols can be developed which overcome the defects we identify. We will also determine the mechanism of adjuvant effects so that better adjuvants can be developed in the future. These studies will generate important information that should contribute to the development in future of better strategies to effectively vaccinate the elderly.